Chronic alpha1 antagonism effect on HPA dysfunction

[Jules]

HPA dysfunction in the form of hypoactive HPA axis or hypocortisolism –

Two similar studies by M. Kabbaj et al showed that chronic treatment with alpha 1 antagonist prazosin reduced hippocampal corticosteroid receptors and increased cort. response to stress. In particular, high responder rats did were not affected, but low responder rats, which had increased brain MR/GR and more efficient negative feedback, were affected (decreased cort. receptors and increased cort. response). In the other study, rats adrenalectomized and sub. with cort. who were treated with praz. chronically, showed a reduction in hippocampal MR levels, while adrenal-intact rats showed a reduction in hippocampal GR, and enhanced cort. responses following stress.

Another study was done where chronic treatment with prazosin to early abstinent alcoholics for 5 weeks seemed to reverse the blunted HPA response to stressors.
After 5 weeks with the alpha 1 antagonist, the praz. group was tested with stressors and showed a robust cort. response, in comparison to the placebo group which showed blunted response. It is said that HPA dysfunction in early abstience is marked by blunted HPA responses to stress and this increases relapse risk. The author of the study attributed the cort. response to higher NA levels as a response to blockade, but did not consider the possibility that maybe praz. was somehow affecting CRh or hippocampal corticosteroid receptors involved in the feedback system. The two groups showed identical cort levels prior to stress test, and only the praz. group produced healthy cort responses to the stressors.

Many veterans with PTSD use this drug and find it to be helpful for aspects of their condition, mainly helping to sleep and have less nightmares. It has ugly side effects such as fainting and dizziness which probably limits its use.

What does chronic blockade of alpha-1 adrenergic receptors do to the HPA axis? Could it be helpful in the hypoactive HPA observed in many cases, such as CFS, PTSD where enhanced negative feedback is one of the key features.

My background: I quickly developed hypocortisolism after my discontinuance with a SNRI, 10 mths (venlafaxine, 150mg). Before this, I was an energetic healthy young woman, never on medication or with any psychiatric or health issues. The drug was given to me by my GP during a very stressful time. On this drug I had hypertension and alot of energy, once off it my BP remained 80s/50s for a year and i had NO metabolism- it was frightening. I have searched high and low for reasons. I was diagnosed by two MDs as hypocortisol and eventually after a year of no change, put on low-dose HC. Detailed workup yielded nothing except extremely low cortisol levels (and mild neutropenia), which leaves me with exhaustion, inflammation, dizziness, and pronounced hypothyroid symptoms in the absence of a thyroid problem. Once on HC, dizziness and hypoglycemia lessened, and body temp came up from 94F to 98F. It helps symptoms a little but not alot. The amazing thing is that I went from one extreme, to the other, nearly overnight, once I was weaned off of venlafaxine. I do believe this is the cause of my pronounced hypocortisol state.

From what I have read via Pubmed, SSRIs and SNRIs are observed to increase hippocampal MR/GR and decrease CRH expression with chronic treatment. They tend to reverse hypercortisolism drive seen in melancholic type depression. They are also useful in hypocort. states since they increase monoamine levels which stimulate the HPA axis. But what causes the severe HPA dysfunction once they are discontinued? Especially if there was no dysfunction prior. This is a big unanswered question. I have encountered many hundreds who became very hypocortisol after coming off of these medications, and end up with a diagnosis of CFS. No one seems to know what has happened, how, why.
Worse yet, there don’t seem to be many solutions. I myself, don’t have any viruses, infections, autoimmune conditions, nutritional deficiencies, allergies, heavy metals etc… all ruled out. My body just produces very little cortisol after coming off of venlafaxine. Where when I was on it, it was healthy and if anything possibly excessive. There are not many solutions to HPA dysfunction. Lifestyle change, diet change, vitamins, often it doesn’t work. Stimulants work but then you can’t stop taking them. And in some cases, they even might peter out. There doesn’t seem to be anything which increases cortisol with chronic/long-term treatment.

Have you ever observed severe hypocortisolism in PTSD, and seen whether chronic treatment with prazosin has helped the patient to generate healthier cortisol levels over time? What in general do you think about these studies and this mechanism. The mechanism is not well-understood or explained in the studies.

I spoke with one of the researchers of the two studies done on the rats, and they said that this drug does show promise in HPA dysfunction, but there is no money for more studies, or studies on humans. this is an old drug, and its already being used in PTSD simply because NA drive is observed to be hyperactive in PTSD.

If you haven’t, I urge you to read the three studies mentioned, or if you have observed much experience with this drug, share what you can about it and what your opinion is on the possible mechanism involved.

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